NM_006265.3:c.1162-7_1162-6dupTT

Variant names:

• chr8-116852713-T-TAA
• rs369816312
• NM_006265.3:c.1162-7_1162-6dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_006265.3(RAD21):​c.1162-7_1162-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,167,612 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (0 hom.)
• Consequence: RAD21 NM_006265.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 3 publications found

Genes affected

RAD21 (HGNC:9811): (RAD21 cohesin complex component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

RAD21 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Mungan syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00102 (138/135358) while in subpopulation AMR AF = 0.00267 (36/13492). AF 95% confidence interval is 0.00198. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 138 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006265.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD21	NM_006265.3	MANE Select	c.1162-7_1162-6dupTT		splice_region intron	N/A	NP_006256.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD21	ENST00000297338.7	TSL:1 MANE Select	c.1162-7_1162-6dupTT		splice_region intron	N/A	ENSP00000297338.2
	RAD21	ENST00000517749.2	TSL:1	c.1162-7_1162-6dupTT		splice_region intron	N/A	ENSP00000430273.2
	RAD21	ENST00000523986.6	TSL:2	n.2492_2493dupTT		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 138 AN: 135316 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000938

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000534

GnomAD2 exomes AF: 0.00170 AC: 148 AN: 87152 AF XY: 0.00165

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00201

Gnomad EAS exome AF: 0.00126

Gnomad FIN exome AF: 0.000936

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.00213 AC: 2202 AN: 1032254 Hom.: 0 Cov.: 2 AF XY: 0.00209 AC XY: 1059 AN XY: 507726

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00344 AC: 76 AN: 22108

American (AMR) AF: 0.00195 AC: 37 AN: 19014

Ashkenazi Jewish (ASJ) AF: 0.000717 AC: 12 AN: 16734

East Asian (EAS) AF: 0.000587 AC: 16 AN: 27248

South Asian (SAS) AF: 0.00365 AC: 158 AN: 43328

European-Finnish (FIN) AF: 0.000823 AC: 30 AN: 36442

Middle Eastern (MID) AF: 0.000769 AC: 3 AN: 3900

European-Non Finnish (NFE) AF: 0.00216 AC: 1775 AN: 821328

Other (OTH) AF: 0.00225 AC: 95 AN: 42152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00102 AC: 138 AN: 135358 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 69 AN XY: 65278

African (AFR) AF: 0.000431 AC: 16 AN: 37162

American (AMR) AF: 0.00267 AC: 36 AN: 13492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3238

East Asian (EAS) AF: 0.00 AC: 0 AN: 4714

South Asian (SAS) AF: 0.000942 AC: 4 AN: 4248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00131 AC: 81 AN: 61942

Other (OTH) AF: 0.000530 AC: 1 AN: 1886

Alfa AF: 0.000330 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369816312; hg19: chr8-117864952;